An enzymatic activity unique to neoplastic cells remains elusive. However, important quantitative differences in enzyme activity between normal and malignant tissues are well known. Knox, W. E. (1976) Enzyme Patterns in Fetal, Adult, and Neoplastic Rat Tissue; S. Karger Basil. Switzerland. These differences form the basis for the selectivity of currently employed antineoplastic drugs. Alkylating agents are among the most potent and toxic anticancer drugs currently in clinical use. The oncospecificity of alkylating agents resides largely in the increased susceptibility of the DNA of rapidly proliferating cells to alkylation. Other factors such as differences in protective glutathione levels and DNA repair activity are also important.
Despite the major advances in clinical cancer therapy due to alkylating agents, drugs of this class have severe limitations. The major problem is one of nonspecific toxicity. There have been numerous attempts to develop alkylating agents which are selectively targeted to tumor cells. Thousands of derivatives have been synthesized and tested for selective antitumor activity. With few exceptions the results have been uniformly discouraging. For example, alkylating agents which are activated by enzymes present in tumor tissue such as alkaline phosphatase, azo-reductase, glucuronidase, plasmin, and collagenase have been explored. Ross, W. C.; Warwick, G. P.; Roberts, J. J.; J. Chem. Soc, 3100 (1955). Connors, T. A.; Foster, A. B., Tisdale, M. J.; (1972) Biochem, Pharmacol, 21:1309 . Connors, T. A.; Whisson, M. E.; (1966) Nature 210:866 Ball, C. R.; Double, J. A.; (1974) Biochem, Pharmacol 23:3173. Workman, P.; Double, J. A.; (1977) Biochem, Pharmacol, 27:199. Marquissee, M. J.; Kauer, J. C. (1978); J. Med. Chem,; 21:1188 Chakravarty, P.; Carl, P.; Weber, M.; Katzenenellenbogen, J.; (1983); J. Med. Chem.; 26:633; and 26:638 The fundamental problem remains one of tumor specificity. Although the tumor may have many fold higher levels of the target enzyme normal tissues also invariably possess some of the enzyme which ultimately activates the alkylating agent and results in toxicity. This severely limits tumor selectivity.